RANBP2

Inheritance Pattern: AD

Disease ID:MONDO:0011953

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0011953

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011953

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0011953

Submitter: ClinGen

Individuals with monoallelic variants in the *RANBP2* gene and features of acute necrotizing encephalopathy (ANE) were first reported in the literature in 2009 (Neilson et al., PMID:19118815). ANE is characterized by a variable presentation of encephalopathy, seizures and potential coma shortly after infection in otherwise healthy and cognitively typical individuals. ANE is also notable for characteristic MRI findings of polyfocal lesions in the thalami, pons and brainstem. Of note, there have been additional individuals reported with *RANBP2* variants in large autism cohorts (PMIDs: 35982160, 28714951). Due to limited phenotypic information about these individuals, we are opting not to include them in this curation for ANE. In multiple reports of patients with ANE and variants in *RANBP2*, a recurrent p.Thr585Met (c.1880C>T) variant is present. This variant has been identified as de novo in some individuals with ANE and has also been identified to segregate with disease in some families (PMIDs: 19118815, 19811512, 20570537, 21945312, 26110162, 34377735). Although typically found in the heterozygous state, at least one publication identifies an individual with disease who carries this variant in the homozygous state (PMID: 36029610). Other missense variants are present in individuals with disease, but with limited additional evidence (PMID:19118815, 20473521, 25170550). No experimental data supporting a relationship between *RANBP2* and ANE has been included in this curation. Of note, given the low penetrance associated with this condition, additional supporting data is needed to further establish a conclusive gene-disease relationship. In summary, there is moderate evidence to support the relationship between *RANBP2* and acute necrotizing encephalopathy. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date April 2, 2024 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between RANBP2 and Leigh syndrome spectrum (LSS) was evaluated using the ClinGen Clinical Validity Framework as of August 17, 2020. The RANBP2 gene encodes RAN-binding protein 2, a nuclear pore complex component that has been annotated as an E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I. The nuclear pore complex spans the nuclear envelope and allows the flow of molecules (proteins, RNA, carbohydrates, lipids and signaling molecules) between the nucleus and cytoplasm. The RANBP2 gene was first reported in relation to autosomal dominant Leigh syndrome spectrum in 2015 (PMID: 26110162). Pathogenic variants in RANBP2 are more commonly associated with acute necrotizing encephalopathy (ANE), however biochemical testing is typically not pursued in these cases as features arise in the setting of a viral illness. Indeed, RANBP2-related disorders are thought to arise due to a combination of a genetic and viral insult. Furthermore, ANE has distinctive histopathological and imaging features, with lesions that may affect the basal ganglia, brainstem, and, most frequently, the thalamus. Therefore, imaging studies may prompt/indicate a potential overlap with the diagnosis of LSS. However, unlike lesions in LSS, the core of the lesions associated with ANE, particularly those in the thalamus, are usually composed of significant perivascular hemorrhage and necrosis of neurons and glial cells. Evidence supporting the gene-disease relationship between RANBP2 and LSS includes case-level data and experimental data. This curation included one variant identified in one case in one publication (PMID: 26110162). No segregation data were available. The exact mechanism of disease is uncertain. This gene-disease association is also supported by expression data and functional alteration in non-patient cells (PMIDs: 18853439, 17887960). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 17, 2020 (SOP Version 7).